Lactose is widely used as a filler, filler-binder or diluent in tablets and capsules, and to a more limited extent in lyophilized products, infant food formulas, and as a carrier for dry powder inhalers. Worldwide, Pharmacopoeia have laid down requirements in their lactose monographs on the identity and purity of pharmaceutical grade lactose, thereby distinguishing between lactose monohydrate and anhydrous lactose. According to these pharmacopoeia, anhydrous lactose should have a water content of at most 1 wt % and is for that reason particularly useful as excipient in moisture-sensitive applications.
In solution, lactose exists as an equilibrium of approximately 60% β-lactose and 40% α-lactose, the two stereoisomers being differentiated by the orientation of the hydroxyl group at carbon atom 1 in the glucose ring of lactose. Upon crystallisation below 93.5° C. α-lactose monohydrate crystals are formed. Above 93.5° C., β-lactose crystallises.
Crystalline β-lactose is an anhydrous non-hygroscopic form meeting the aforementioned criterion of low water content. Under stringent conditions thermal dehydration or desiccation of α-lactose monohydrate crystals may also yield anhydrous modifications, in most cases a mixture of stable and unstable anhydrous lactose.
Anhydrous lactose is conventionally produced by roller drying and comprises more than 70% crystalline β-lactose, such as described by Lerk et al. in Physico-Pharmaceutical Properties of Lactose; Proceedings of the International Colloquium on Industrial Pharmacy (1983) pages 59-88. U.S. Pat. No. 3,802,914 discloses an alternative route of spraying a lactose solution onto a revolving heated drum at high temperature, thereby yielding an anhydrous lactose high in β-lactose.
GB-A-2.077.268 teaches a process for producing anhydrous stable lactose, wherein crystalline α-lactose monohydrate is introduced as a dry product into an extruder, the jacket of which is heated to a temperature above 100° C., and the lactose is then extruded. Temperatures of 162 and 164° C. are exemplified. This method yields anhydrous lactose high in β-lactose, which can be used to manufacture tablets, but it is not agglomerated, and the lactose so prepared shows relatively high bulk density and low compactibilities. Therefore, tablets prepared from the anhydrous stable lactose according to GB-A-2.077.268 can only resist pressures of 10-13 kg. These numbers can be expressed in terms of tablet strength at 10 kN compression force, as used in the application, to give a tablet strength of about 75 N.
Anhydrous β-lactose is not to be confused with spray-dried lactose as for instance disclosed in U.S. Pat. No. 3,639,170 or EP-A-239.172. Spray-dried lactose is a hygroscopic form consisting of spherical particles of small α-lactose monohydrate crystals glued together in an amorphous lactose matrix and typically containing less than 20% of β-lactose. Because of its high α-lactose monohydrate content spray-dried lactose shows limited compactibility. Moreover, its total water content of about 5 wt % makes it unsuitable for many moisture-sensitive applications.
Because of its much better compactibility compared to α-lactose monohydrate or spray-dried lactose, anhydrous β-lactose is a preferred excipient in the pharmaceutical industry. However, the fluidity of roller-dried anhydrous β-lactose is usually poor, thus resulting in a wide weight variation and inhomogeneities within the final product owing to variable fill.
In order to improve its flowability, β-lactose is therefore commonly subjected to a sieving step to remove fines and obtain a coarser grade, Pharmatose DCL22 by DMV International B.V. (Veghel, The Netherlands) being a good example thereof. A drawback of such a sieving step is that improved flowability is realised at the cost of wasting valuable finely divided material. Further, the anhydrous lactose thus obtained has only limited compactibility, especially unfavourable in formulations with a high drug dosage.
Therefore, the need exists for a process for the preparation of a directly compressible β-lactose with a high percentage of β-lactose which is anhydrous (less than 1% moisture w/w), having better compactibility properties compared to regular anhydrous β-lactose, but also exhibiting good flow characteristics, and without the loss of fines during preparation.